The purpose of this research (a project of the CORESTA Biomarkers Sub-Group) was to establish a population level estimate for the biomarker of cigarette smoke exposure, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), to serve as a baseline against changes in exposure. We conducted a meta-analysis based on published literature between 2008-2020. A protocol for literature assessment was developed, followed by an evidence-based table to identify and select studies. The data template identified elements in four major categories: Study identification, Study Design, Results, and Demographics.

A total of 76 scientific articles were identified and reviewed for potential inclusion resulting in 42 studies that met the pre-set criteria (reported clinical studies and/or observational studies with reportable original values). The dataset was normalized to pmol/mg creatinine, a unit most commonly used in research studies. This was accomplished with the use of a “conversion template” based on parameters and assumptions (e.g. healthy individuals with average creatinine excretion of 2.208 gm/day (0.601-2.936 gm/day)). Total NNAL reported as “geometric” mean (excluding “median”) were considered that resulted in 19 studies for the statistical evaluation. The database was organized by categories, filtered, and data was weighted according to the size of the groups. Most of the data was derived from smokers (n=12,218) followed by non-smokers (n=1,160).

Smokers had the highest level of NNAL (1.112 pmol/mg creatinine; 95 % CI 0.161-2.047) compared to non-smokers (0.008 pmol/mg creatinine; 95 % CI 0.001-0.017). Statistical analysis indicated that the two groups are significantly different (p < 0.0002). This research establishes population level estimate for NNAL levels that can be used to determine changes in exposure for smokers switching to potentially reduced-risk tobacco products (RRPs).